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A Systematic Review of the Efficacy of Centella asiatica for Improvement of the Signs and Symptoms of Chronic Venous Insufficiency

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  • University Malaya and MAHSA University

Abstract and Figures

We aimed to assess the efficacy of Centella asiatica for improvement of the signs and symptoms of chronic venous insufficiency (CVI). We searched 13 electronic databases including the Cochrane Central Register of Controlled Trials for randomised controlled trials assessing the efficacy of Centella asiatica for CVI. Two review authors independently selected studies, assessed the risks of bias of included studies and extracted data. The treatment effects of similar studies were pooled whenever appropriate. Eight studies met the inclusion criteria. The pooling of data of similar studies showed that Centella asiatica significantly improved microcirculatory parameters such as transcutaneous partial pressure of CO2 and O2, rate of ankle swelling and venoarteriolar response. Three out of the eight studies did not provide quantitative data. However, these studies reported that patients treated with Centella asiatica showed significant improvement in CVI signs such as leg heaviness, pain and oedema. Our results show that Centella asiatica may be beneficial for improving signs and symptoms of CVI but this conclusion needs to be interpreted with caution as most of the studies were characterised by inadequate reporting and thus had unclear risks of bias, which may threaten the validity of the conclusions.
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Evidence-Based Complementary and Alternative Medicine
Volume , Article ID ,  pages
http://dx.doi.org/.//
Review Article
A Systematic Review of the Efficacy of Centella asiatica
for Improvement of the Signs and Symptoms of Chronic
Venous Insufficiency
Nyuk Jet Chong and Zoriah Aziz
Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
Correspondence should be addressed to Zoriah Aziz; zoriah@um.edu.my
Received  July ; Accepted  December 
Academic Editor: Yoshiyuki Kimura
Copyright ©  N. J. Chong and Z. Aziz. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
We aimed to assess the ecacy of Centella asiatica for improvement of the signs and symptoms of chronic venous insuciency
(CVI). We searched  electronic databases including the Cochrane Central Register of Controlled Trials for randomised controlled
trials assessing the ecacy of Centella asiatica for CVI. Two review authors independently selected studies, assessed the risks of bias
of included studies and extracted data. e treatment eects of similar studies were pooled whenever appropriate. Eight studies met
the inclusion criteria. e pooling of data of similar studies showed that Centella asiatica signicantly improved microcirculatory
parameters such as transcutaneous partial pressure of CO2and O2, rate of ankle swelling and venoarteriolar response. ree out
of the eight studies did not provide quantitative data. However, these studies reported that patients treated with Centella asiatica
showed signicant improvement in CVI signs such as leg heaviness,p ainand o edema. Our results show that Centellaasiatica may be
benecial for improving signs and symptoms of CVI but this conclusion needs to be interpreted with caution as most of the studies
were characterised by inadequate reporting and thus had unclear risks of bias, which may threaten the validity of the conclusions.
1. Background
e term chronic venous insuciency (CVI) describes a
condition that aects the venous systems of the lower limbs.
It results from the obstruction or reux of blood ow in the
veins due to abnormalities of the venous wall and valves [].
Because of the abnormalities, venous blood ow is bidirec-
tional, resulting in inecient venous outow and high venous
pressure []. Symptoms of CVI may include leg discomfort,
heaviness, cramps, pains, oedema, and skin changes. e
most serious consequence of CVI is venous ulcers. CVI
causes considerable cost to society in terms of diagnosis,
treatments, loss of working hours, and impairment of quality
of life [,].
CVI is one of the most common diseases in the world [].
However, the exact prevalence in any population is dicult to
determine due to the limited availability of population-based
epidemiological studies. Some studies examined specic
groups or samples of hospital patients [,], while others
focus only on specic conditions such as varicose veins
or leg ulcers. Additionally ill-dened classications of CVI
make prevalence data dicult to interpret. Nevertheless, the
prevalenceofCVIisbelievedtobehighinwesternand
industrialised countries [,].
e aetiology of CVI is unclear, although it has been
knownthatitoccurswhenvenousbloodtransportisdis-
turbed in supercial or deep venous systems, the perforating
veins, or both []. Changes in the hemodynamics of the large
veins of the lower limbs are transmitted into the capillary
bed (microcirculation) and eventua lly results in chronic dam-
age and microcirculatory dysfunction []. is dysfunction,
also termed as venous microangiopathy, is associated with
increased capillary permeability which leads to the accumu-
lation of uid and becomes evident as oedema. e concept
Evidence-Based Complementary and Alternative Medicine
of venous microangiopathy permits the quantication of
microcirculatory parameters in CVI [].
Recently, several indirect tests have become available
which can provide quantitative assessment of the microcir-
culatory changes associated with CVI [,]. Changes in skin
ux and other microcirculatory parameters such as tran-
scutaneous partial pressure of oxygen (tcPO2), carbon diox-
ide (tcPCO2), capillary ltration rate (measured as rate of
ankle swelling), and venoarteriolar response (VAR) are use-
ful measures in the evaluation of venous microangiopathy
[]. For example, the tcPO2is decreased while tcPCO2is
increased in subjects with venous microangiopathy [].
Existing interventions that have been proven, or are likely,
to be therapeutically benecial in the treatment of CVI
include limb elevation, surgery and mechanical compression
[]. Use of compression stockings is common for the
management of venous insuciency. However, poor compli-
ance is a well-known problem with compression stockings.
Additionally some patients are unable to use compression
stockings due to the condition of their limbs or their general
health [].
ere has been considerable interest in the role of phar-
macological agents to treat CVI. A number of drugs have
been used as adjunctive therapies in treatment of CVI includ-
ing aminaone and calcium dobesilate [,]. However,
there is not enough evidence to support the ecacy of these
agents for CVI [].
Plant constituents which have been evaluated for the
treatment of signs and symptoms of CVI and venous micro-
angiopathy include diosmin, avonoids, and saponosides
[]. Even though these plant constituents have been
shownintheshorttermtobeeectiveatreducingpainand
oedema related to symptoms of CVI, their long-term ecacy
has not been established [,]. One herb that has received
substantial attention for improving signs and symptoms of
CVI and microangiopathy of the lower limbs is Centella
asiatica [,]. e leaves of Centella asiatica contain triter-
penes which have been shown in animal studies to have anti-
inammatory properties [,] and promote wound healing
by stimulating collagen and glycosaminoglycan synthesis as
well as angiogenesis [,].
Several non systematic reviews have reviewed various
aspects of Centella asiatica including the chemistry, pharma-
cology, and clinical uses [,,]. However, none of
thesereviewsfocusedontheevidencefortheuseofCentella
asiatica in CVI. For this reason, it was necessary to do an
objective and rigorous assessment of the evidence for the
ecacy of Centella asiatica for CVI.
2. Methods
2.1. Selection of Studies. We only considered randomised con-
trolled trials (RCTs) examining or describing the eectiveness
of Centella asiatica for improving signs and symptoms of
CVI and microangiopathy compared with placebo, standard
therapy or other active agents. Even though most of the
RCTs do not use specic diagnostic classication of CVI, we
included studies which recruited patients with CVI or venous
hypertension. We excluded studies assessing Centella asiatica
in combination with other active agents as well as studies
which recruited subjects with postthrombotic syndrome or
passengers on long ights.
2.2. Identication of Studies. We carried out a comprehensive
literature search for RCTs published from  to June 
withnorestrictiononthesourceandlanguageofthepublica-
tions. e search included  electronic databases and cross-
referencing of articles. Among the databases searched were
OVID, Cochrane Library, MEDLINE, PubMed, MEDICAL
Databases @EBSCOhost, and Scopus. We also did hand
searches on publications published in English.
2.3. Data Collection and Risk of Bias Assessment. Two r e view
authors independently assessed the eligibility of studies from
the searches. Full reports of potentially eligible studies were
obtained for data extraction and assessment of their risk
of bias. Data were extracted using a prespecied extraction
form.
We extracted outcome data that reported any of the clin-
ical signs and symptoms of CVI such as leg oedema, skin
changes, leg discomfort (tingling, burning, itching, sensa-
tions of throbbing, or heaviness), and pain. Outcome data
which assessed microcirculatory parameters of microangio-
pathy such as rate of ankle swelling (RAS), tcPO2, tcPCO2,
and VAR were also extracted. We also extracted data on
adverse eects.
We assessed the risk of bias in the included studies based
on criteria published in the Cochrane Handbook for System-
atic Reviews of Interventions []. Any disagreements at the
stages from selecting studies to data extraction and risk of
bias assessment were resolved through discussions between
the two review authors.
2.4. Data Synthesis. e studies included in the review were
combined by narrative overview with a quantitative summary
of the results of similar trials if appropriate. Data pooling
of continuous data was performed using the weighted mean
dierence.
3. Results
3.1. Results of the Search. e search of  electronic databases
and various sources identied  potentially relevant articles
on Centella asiatica for CVI and microangiopathy (Figure ).
We screened the titles and abstracts for relevance and
excluded  studies. Out of the  full articles retrieved for
further evaluation, we excluded another eight studies. e
studies were excluded because they involved diabetic patients
[,], patients with postthrombotic syndrome [], ight
passengers [], nonrandomised controlled trial [], and
review papers [,,].
3.2. Description of the Studies. A total of eight studies met
the inclusion criteria: three recruiting patients with venous
insuciency of the lower limbs []andveinvolving
patients with venous hypertensions of the lower limbs []
(Table ).esamplesizesrangedfromtowithmean
sample size of  and median . e duration of the trials
Evidence-Based Complementary and Alternative Medicine
225 records screened 209 records excluded
16 full-text articles assessed for eligibility 8 full-text articles
excluded with reasons
8 studies included in qualitative synthesis
5 studies included in quantitative synthesis
863 records aer removing duplicates
949 records identied
through database
searching
Included Eligibility Screening Identication
638 records excluded
37 additional records
identied through other
sources
F : Flow chart of result of searches, studies identied and included in this paper.
T : Characteristics of RCT on CVI and microangiopathy included in this study.
Study Participants Intervention (dose) 𝑛Duration of
study Control
Allegra et al.,  []Patients with venous
insuciency of the lower limbs TTFC A ( mg/day)   days placeb o
Marastoni et al.,  []PatientswithCVI Centella asiatica extract
(tid)  weeks tribenoside
Pointel et al.,  []Patients with venous
insuciency of the lower limbs TTFCA ( mg;  mg)   weeks placebo
Cesarone et al.,  []Patients with chronic venous
hypertensive microangiopathy
TTFCA ( mg bid;
 mg bid)   days placebo
Cesarone et al.,  []
Patients with severe venous
hypertension, ankle swelling, and
lipodermatosclerosis
TTFCA ( mg bid)   weeks placebo
Cesarone et al.,  []
Patients with venous
hypertension with ankle and foot
swelling, oedema, and
lipodermatosclerosis, with intact
skin
TTFCA ( mg bid)   weeks placebo
De Sanctis et al.,  []
Patients with venous
hypertension (ambulatory
venous pressure > mm Hg)
TTFCA ( mg tid;
 mg tid)   weeks placebo
Incandela et al.,  []Patients with venous
hypertensive microangiopathy
TTFCA ( mg daily;
 mg daily)   weeks placebo
TTFCA: total triterpenic fraction of Centella asiatica.
Extract dosage not reported.
ranged from  to  days. Four studies were conducted in
Europe: Italy [,], France [], and UK [], while three
other studies [] published by authors from Italy and UK
did not provide the setting of their studies.
3.3. Risk of Bias in Included Studies. e risk of bias in
the included studies is summarised in Figure .Adequate
sequence generation was reported in two trials [,]; the
other six trials have an unclear risk of bias from sequence
generation. In these six trials, there was no description of
how randomisation was achieved even though the authors
described the studies as RCT. e lack of description of the
allocation process also meant that the allocation concealment
was unclear.
In judging the risk of bias from blinding, we considered
who was blinded in the trial. We considered four trials
[,,,] to have a low risk of bias from blinding of
participants as participants in both treatment and control
groups received similar looking tablets. We were unable to
judgetheriskofbiasduetoblindinginfourothertrials
Evidence-Based Complementary and Alternative Medicine
Adequate sequence generation
Allocation concealment
Blinding (participant)
Blinding (care provider)
Blinding (outcome assessor)
Incomplete outcome data addressed (ITT)
Free of selective outcome reporting
Financial support
Group similar at baseline
Allegra et al., 1981 [38]
Marastoni et al., 1982 [39]
Pointel et al., 1987 [40]
Cesarone et al., 1994 [41]
Cesarone et al., 2001a [42]
Cesarone et al., 2001b [43]
De Sanctis et al., 2001 [44]
Incandela et al., 2001 [45]
+++
++
+
+
+
+?
+
+++
++
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? ? ? ? ?
?
?
?
?
?
+? ??
? ? ? ????
????
? ? ? ? ?
?? ? ? ? ?? ?
? ? ????
?
?
?
+
+
+
+
+
Note: ITT: “intention-to-treat” analysis; indicates low risk of bias; indicates unclear risk of bias
+ ?
F : Risk of bias summary.
[,,,] as these trials did not provide information on
whether the participants, care provider, and outcome assessor
were blinded.
In judging the risk of bias from incomplete outcome
reporting, we considered whether missing data were imputed
appropriately and whether an intention-to-treat analysis was
reported for the outcomes. Only three trials [,,]were
considered to have low risk of bias from incomplete outcome
data.esetrialshavenolosstofollowup(dropout).Allthe
participants in these trials were reported to demonstrate very
good compliance and tolerance of Centella asiatica treatment
as no participants le the study before its completion. ere
was no information on the numbers lost to followup in one
trial []. Dropouts were reported in four other studies [
,]. In two, these were due to side eects experienced with
Centella asiatica [,].
Selective outcome reporting has been dened as the selec-
tive reporting in a publication of only a selection of outcomes,
perhaps those based on statistically signicant results [].
In considering the risk of bias from the selective reporting,
we based our assessment on comparing outcomes listed
in the methods section of the paper with those outcomes
reported in the results section. None of the trials reported
the availability of the study protocol. Overall, the method
sections of the trials included did not explicitly state the
primary and secondary outcomes. One study []didnot
report all the outcomes which were mentioned in the method
section while two studies [,] reported several outcomes
which were not mentioned in the method section. us, we
considered these three studies to have unclear risk of bias
for selective reporting. We judged the risk of bias from the
selective reporting in the other ve trials [,]tobe
low.
Wefocusedontwootherimportantaspectsofother
potential sources of bias that could threaten the validity of the
study’s ndings. e two risks were baseline comparability
andnancialsupportreceivedbythetrial.Fivetrials[]
wereconsideredtobeatlowriskofbiasfrombaselinecom-
parability as there was no signicant dierence in baseline
between the treatment and control groups, while the risk of
this bias was not clear for the other three studies. None of the
eight studies provided information on the nancial support
for the study, and therefore we were unable to judge the risk
of bias due to sponsorship.
3.4. Eects of the Intervention. Even though most of the
included trials reported the eectiveness of Centella asiatica
in improving the signs and symptoms of CVI and microan-
giopathy compared to control, the ndings were dicult
to interpret as various outcome measures were used to
assess eectiveness. Several trials used subjective assessment
measures such as oedema, varicose veins, and leg heaviness
while other trials used objective measure of microcirculatory
Evidence-Based Complementary and Alternative Medicine
T : Outcomes assessed.
Study Outcome measures Conclusion
Allegra et al.,  []
Pain, heaviness, leg oedema,
trophic lesions, easy tiredness,
skin hypothermia, varicosities,
and tolerance
Improves venous reux in
patients
Marastoni et al.,  []
Night cramps, painful limbs,
numbness, heaviness, orthostatic
oedema, and altered skin
trophism
Improves clinical observations of
venous insuciency and venous
tone
Pointel et al.,  []
Venous distensibil it y, % o f
patients with improved heaviness
in legs, oedema, and standing leg
pain
TTFCA is well tolerated and
superior to placebo in the
treatment of venous insuciency
Cesarone et al.,  []RF,tcPCO
,andtcPO
Eective in venous hypertensive
microangiopathy
Cesarone et al., a [] RF, CFR (measured as RAS)
Improves microcirculation with
venous hypertension and venous
microangiopathy
Cesarone et al., b []RF,VAR,tcPCO
,tcPO
,andRT
Improves microcirculation and
leg volume in venous
hypertension
De Sanctis et al.,  [] CFR, RT
Reduces the increased capillary
ltration in patients with venous
hypertension
Incandela et al.,  [] BRF, VAR, tcPCO,andtcPO
Useful for treatment of venous
hypertensive microangiopathy
BRF: baseline resting ow.
CFR: capillary ltration rate.
tcPCO: transcutaneous pressure of carbon dioxide.
tcPO: transcutaneous pressure of oxygen.
RAS: rate of ankle swelling.
RF: resting ux.
RT: relling time.
VAR: venoarteriolar response.
parameters such as tcPCO2, tcPO2,andRAS(Ta b l e  ). We
categorisedtheresultsintothefollowing.
3.4.1. Signs and Symptoms of CVI. ree trials [,,]
assessed treatment outcomes such as leg heaviness, oedema,
and pain but did not provide quantiable data. ese trials
reported qualitatively that the Centella asiatica group showed
signicantly greater improvement compared to the control
group in treating the signs and symptoms of CVI.
3.4.2. Microcirculatory Parameters. Two trials [,]pro-
vided data for rate of ankle swelling, but they were not
suciently homogenous for the data to be pooled. erefore,
we presented the data separately for each trial. Figures (a)
and (b) show there was a statistically signicant eect on
ankleswellinginfavourofTTFCAgroupaereightweeksof
treatment (MD .; % CI . to .) and four weeks
of treatment (MD .; % CI . to .), respectively.
e tcPO2and tcPCO2values were reported in three trials
[,,]involvingsubjects.etrialsweresuciently
homogenous to allow us to pool the results. Figure (c) shows
that the increase in tcPO2was signicantly higher in the
TTFCA group compared to the control group (WMD .;
%CI.to.)whileFigure (d) shows the decrease in
tcPCO2was signicantly greater favouring the TTFCA group
(WMD . ;  % C I . to .).
Only two studies [,]evaluatedVARusinglaser
doppler owmetry. One trial []involvingsubjects
provided quantiable data on VAR. Figure (e) shows there
was a statistically signicant eect on VAR in favour of
TTFCA group (MD ; % CI . to .).
3.5. Adverse Eects. Two trials reported on the adverse
eects [,]. Two patients given Centella asiatica extract
experienced minor stomach pain while one patient had to
stop treatment due to severe nausea []. Four patients given
TTFCA withdrew from the trial []: three due to nausea and
gastric pain and one because of “neurological absence.”
4. Discussion
isistherstpaperthatusesasystematicreviewmethod-
ology to evaluate the ecacy of Centella asiatica for the
management of the signs and symptoms of CVI. Except for
Evidence-Based Complementary and Alternative Medicine
21012
Favours TTFCA Favours placebo
Study
Total (95% CI)
Heterogeneity: not applicable
mean (SD) 𝑁𝑁
22
22
mean (SD)
0.11 (0.16) 18
18
Weight
100.0%
100.0%
IV, xed, 95% CI
TTFCA Placebo Mean dierence Mean dierence
IV, xed, 95% CI
0.84 [
0.94,
0.74]
0.84 [ 0.94, 0.74]
Cesarone et al., 2001 [42] − 0.73 (0.17)
Test for overall eect: 𝑍= 16.06 (𝑃< 0.00001)
(a)
21012
Favours TTFCA Favours placebo
Study
Total (95% CI)
Heterogeneity: not applicable
mean (SD)
20
20
mean (SD)
20
20
100.0%
100.0%
IV, xed, 95% CI
TTFCA Placebo Mean dierence Mean dierence
IV, xed, 95% CI
Weight
Test for overall eect: 𝑍=121.75(𝑃< 0.00001)
0.78 (0.02) 0.01 (0.02) 0.77 [0.78, 0.76]
De Sanctis et al., 2001 [44]
0.77 [0.78, 0.76]
𝑁𝑁
(b)
20 10 0 10 20
Favours placebo Favours TTFCA
Study
Total (95% CI)
mean (SD)
8 (6.59)
4 (12.73)
7 (6.01)
31
20
33
84
mean (SD)
0.9 (7.08)
1 (10.63)
0 (7.30)
27
20
27
74
Weight
43.5%
10.3%
46.2%
100.0%
IV, xed, 95% CI
7.10 [3.56, 10.64]
7.00 [3.57, 10.43]
6.63 [4.30, 8.96]
TTFCA Placebo Weighted mean dierence Weighted mean dierence
IV, xed, 95% CI
Cesarone et al., 1994 [41]
Cesarone et al., 2001 [43]
Incandela et al., 2001 [45]
Test for overall eect: 𝑍=5.57(𝑃< 0.00001)
3.00 [− 4.27, 10.27]
𝑁𝑁
Heterogeneity: 𝜒2= 1.07,df=2(𝑃 = 0.59); 𝐼2=0%
(c)
20 10 0 10 20
Favours placeboFavours TTFCA
Study
Total (95% CI)
mean (SD)
31
20
33
84
mean (SD)
1 (9.22)
27
20
27
74
43.5%
12.5%
44.0%
100.0%
IV, xed, 95% CI
TTFCA Placebo Weighted mean dierence
IV, xed, 95% CI
Weight Weighted mean dierence
Test for overall eect: 𝑍=7.26 (𝑃< 0.00001)
Cesarone et al., 1994 [41]
Cesarone et al., 2001 [43]
Incandela et al., 2001 [45]
8.00 [11.07, 4.93]
4.00 [9.71, 1.71]
8.00 [11.05, 4.95]
− 7.50 [9.52, 5.47]
9 (5.04)
3 (9.22)
9 (4.98)
1 (6.64)
1 (6.72)
𝑁𝑁
Heterogeneity: 𝜒2= 1.65,df=2(𝑃 = 0.44); 𝐼2=0%
(d)
100 50 0 50 100
Favours placebo Favours TTFCA
Study
Total (95% CI)
Heterogeneity: not applicable
mean (SD)
75 (27.1) 33
33
mean (SD)
1 (27.9) 27
27
Weight
100.0%
100.0%
IV, xed, 95% CI
74.00 [59.99, 88.01]
74.00 [59.99, 88.01]
TTFCA Mean dierence
IV, xed, 95% CI
Placebo
Incandela et al., 2001 [45]
Test for overall eect: 𝑍= 10.35 (𝑃< 0.00001)
Mean dierence
𝑁𝑁
(e)
F : (a) Comparison: total triterpenoid fraction of Centella asiatica (TTFCA) versus placebo for eight weeks; outcome: rate of ankle
swelling (mL/min per  mL). (b) Comparison: TTFCA versus placebo for four weeks; outcome: rate of ankle swelling (mL/ mL per
min). (c) Comparison: TTFCA versus placebo; outcome: transcutaneous partial pressure of oxygen (mmHg). (d) Comparison: TTFCA
versus placebo; outcome: transcutaneous partial pressure of carbon dioxide (mmHg). (e) Comparison: TTFCA versus placebo; outcome:
venoarteriolar response (mV).
Evidence-Based Complementary and Alternative Medicine
thehandsearches,therewasarestrictiononthelanguageof
publications. We contacted several authors and researchers
directly for further data on the outcome of interest, but very
few of them responded. e absence of adequate data from
eligible studies for the outcome of interest is a common
problem encountered in most meta-analysis []. We did
not attempt to use several available statistical procedures for
handling missing outcome data because all have weaknesses
[]. Pooling the results of the individual studies would give
larger sample size and therefore increase the statistical power
to determine treatment eects [,]. However, we were
unable to pool the results of several studies because outcome
data were missing.
Measuring the outcomes of interventions in CVI is
dicult. ere is no single test which can serve as a common
index of change following the intervention. Measuring ambu-
latory venous pressure (AVP) which is equivalent to the ankle
arterial pressure is invasive. Several noninvasive physiological
tests which are based on microcirculatory parameters are not
suitable as surrogates for AVP. Besides, current physiological
tests are not standardised and do not provide established nor-
malvaluestogiveanobjectivemeasureofeectsfollowing
treatment.
e outcomes of the treatment of CVI with Centella
asiatica in the trials we have reviewed should be interpreted
with caution as only one trial [] had a low risk of bias from
the blinding of both of the participant and outcome assessor.
Forsubjectivemeasuressuchaspain,theblindingofoutcome
assessor is crucial [].
Improvements in microcirculatory parameters are usu-
ally associated with improved signs and symptoms of CVI
[,]. It is possible that decreased tcPCO2reduces vaso-
dilatation and capillary permeability thus resulting in impro-
vement in oedema []. e results seem to suggest that
TTFCA improves RAS, VAR, tcPO2, and tcPCO2.However,
these ndings should be interpreted with caution since
normal values for these parameters are not well established.
Values that constitute statistically signicant dierences from
pretreatment values between treatment and control group
may not be clinically signicant. e result of this study is
in agreement with other nonsystematic reviews [,]in
that evidence for the ecacy of Centella asiatica extract for
CVIisinconclusive.isisprobablyduetothecomplexityof
measuring outcomes in CVI.
4.1. Limitations. ere were several limitations to our paper.
First, designing a search strategy to locate all trials on
Centella asiatica for CVI and microangiopathy is not easy. We
recognised that we might have missed out studies published
in non-English publications. However, a more comprehensive
hand search for non-English articles would be costly and
time consuming. erefore, these missing studies may have
limited the completeness of our paper.
Second, none of the included studies used the currently
accepted CEAP classication for the diagnosis of CVI. Five
studiesusedspecieddiagnosticcriteriaforCVI[].
However, not all these studies used the same criteria. ree
studies [] did not disclose the criteria used to diagnose
CVI or microangiopathy. erefore, the characteristics of the
subjects included in these studies in terms of degree of pro-
gression of CVI and microangiopathy may be heterogeneous
amongthestudies.iscouldpotentiallyleadtodierences
in response to treatment across the dierent studies.
ird, the studies used dierent measures to assess the
signs and symptoms of CVI as well as dierent physiological
tests to evaluate circulatory parameters following treatment.
Subjectiveoutcomemeasuressuchaspain,oedema,and
heaviness made the interpretation of the results in three trials
dicult. ese trials may be at risk of bias particularly as they
did not adequately report on the methods used to blind the
outcome assessors. Lack of blinding in RCTs has been shown
to be associated with more exaggerated estimates of treatment
eects [].
Fourth,itwasdiculttoassesstheriskofbiasformost
of the included studies. We were unable to verify the required
information from the authors as they did not response to
most of our requests for additional information. erefore,
theriskofbiasinmostoftheincludedstudiesissomewhat
unclear. Sequence generation, allocation concealment, and
blinding are not adequately reported. It is dicult to know
whether this is due to poor design or conduct of the trial.
However, trials that omit important methodological details
have been associated with biased overestimates of treatment
eects [].
Despite these limitations, we have not restricted our paper
to trials with specied methodological characteristics or trials
that report on a particular outcome. e use of narrow
inclusion criteria would have dealt with the heterogeneity
challenges, but we would risk losing information on how
trials on Centella asiatica are conducted and thus would not
be able to highlight the shortcomings of the available trials for
the benet of future trials.
5. Conclusion
e eight trials of Centella asiatica we included in this
paper all reported benecial eects of plant extract on CVI.
However, the extent to which we can draw conclusions
about the benecial eects of Centella asiatica on CVI and
microangiopathy is still limited. ere are some suggestions
of ecacy on some physiological parameters although the
clinical relevance of these results is uncertain due to an
absence of well-established normal values for the circulatory
parameters. e positive eects on the circulator y parameters
of microangiopathy should also be interpreted with caution,
giventhattherisksofbiasinmostofthestudiesareunclear.
Due to the limitations of current evidence, the need for
better quality RCTs to evaluate the ecacy of Centella asiatica
is warranted. Future trials should dene accurately CVI and
microangiopathy using CEAP classications, and the RCTS
should be adequately reported using the CONSORT 
Statement [].
Acknowledgments
e authors are indebted to the authors who have responded
to their request for full-text journal articles or provided
further information on the study. is work was supported
Evidence-Based Complementary and Alternative Medicine
by Postgraduate Research Fund (PS/C) of Institute
of Research Management and Monitoring, University of
Malaya.
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... Betacaryophyllene, germacrene, alpha-pinene [12] Phenols Quercetin, rutin, naringin, castilliferol, kaempferol, luteolin, quercetin-3-o-β-d-glucuronide. [12] Phenols Rosmarinic acid, 1,5-di-o-caffeoyl quinic acid, 4,5-di-o-caffeoyl quinic acid, 3,5-di-o-caffeoyl quinic acid, [13] Phenols Tannin and phlobatannin. [13] A survey conducted by Nayar and Sastry [14] reported the shocking decline of the wild population of C. asiatica due to unchecked and unregulated exploitation of the herb, particularly for medicinal purposes, coupled with the absence of efforts for its organized cultivation. ...
... [12] Phenols Rosmarinic acid, 1,5-di-o-caffeoyl quinic acid, 4,5-di-o-caffeoyl quinic acid, 3,5-di-o-caffeoyl quinic acid, [13] Phenols Tannin and phlobatannin. [13] A survey conducted by Nayar and Sastry [14] reported the shocking decline of the wild population of C. asiatica due to unchecked and unregulated exploitation of the herb, particularly for medicinal purposes, coupled with the absence of efforts for its organized cultivation. Due to a gradual decline in its numbers, its limited cultivation, poor seed viability, and insignificant restoration efforts, the herb has been included in the threatened category by the International Union for Conservation of Nature and Natural Resources (IUCN) and has also been categorized as an endemic species to the Western Ghats of Southern India [15]. ...
... Oxidative stress of the body, urine-excretory system [37] Kaempferol Anti-HIV, anti-inflammatory, iodinate thyronine deiodinase inhibitor, and antioxidant. Reduced immunity [13] Betulic acid Cytotoxic, antibacterial, antineoplastic. Bacterial diseases, tumors [38] Ascorbic acid Antibacterial, antidote, antihypercholesterolemic, antioxidant, and inhibits the release of carcinogen. ...
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Centella asiatica L., commonly known as Gotu kola, Indian pennywort, and Asiatic penny�worts, is an herbaceous perennial plant that belongs to the family Apiaceae and has long been used in the traditional medicine system. The plant is known to produce a wide range of active metabolites such as triterpenoids including asiatic acid, asiaticoside, brahmoside, and madecassic acid along with other constituents including centellose, centelloside, and madecassoside, etc., which show immense pharmacological activity. Due to its beneficial role in neuroprotection activity, the plant has been considered as a brain tonic. However, limited cultivation, poor seed viability with low germination rate, and overexploitation for decades have led to severe depletion and threatened its wild stocks. The present review aimed to provide up-to-date information on biotechnological tools applied to this endangered medicinal plant for its in vitro propagation, direct or indirect regeneration, synthetic seed production, strategies for secondary metabolite productions including different elicitors. In addition, a proposed mechanism for the biosynthesis of triterpenoids is also discussed.
... [79][80][81][82] In addition, other phytocompounds, naringin, kaempferol, and β -pinene were reported to involve anti-inflammatory activity. 24,83,84 Furthermore, asiaticoside is important anti-inflammatory constituents of C. asiatica that presented the strong effect to suppress the production of NO and secretion of TNFα in lipopolysaccharide stimulated RAW 264.7 cells. 85,86 Previously, H. umbellata was reported to have prominent biological activities, such as anti-inflammatory effect. ...
... 101 C. asiatica has also beneficial used for improving cognition in neurodegenerative disorders and microcirculation. 84,102 Many studies support the activity of C. asiatica extracts and individual triterpene compounds in the wound healing process both in vitro and in vivo treatments. C. asiatica has a great impact on extracellular matrix proteins deposition and stimulates fibroblasts proliferation. ...
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Introduction Centella is an important genus in the Apiaceae family. It includes Centella asiatica , which has significant edible and medicinal values. However, this species is easily confused due to its similar morphological traits to Hydrocotyle umbellata , hindering its utilization in the consumer and pharmacological industries. Objective The study aims to differentiate these two closely related plant species using reliable methods of confirming the authenticity of natural herbal medicines. Methods Our work mainly focuses on the basic morphological characteristics, chemical markers, genetic fingerprints, and their biological responses. Results The plants can be clearly differentiated using their leaf shapes, stipules, petioles, inflorescences, and fruit structures. Although the phytochemical compositions of the C. asiatica extract were similar to that of H. umbellata which included flavonoids, tannins, and saponins important to the plant's ability to reduce inflammation and promote healing of wounds, the H. umbellata extract showed significantly higher toxicity than that of C. asiatica . High‐performance liquid chromatography analysis was used to identify chemical fingerprints. The result revealed that C. asiatica had major triterpene glycoside constituents including asiaticoside, asiatic acid, madecassoside, and madecassic acid, which have a wide range of medicinal values. In contrast, triterpenoid saponins were not identified in H. umbellata . Furthermore, using SCoT1–6 primers was possible to effectively and sufficiently created a dendrogram which successfully identified the closeness of the plants and confirmed the differences between the two plant species. Conclusion Therefore, differentiation can be achieved through the combination of morphometrics, molecular bioactivity, and chemical analysis.
... It is often used to treat lung heat cough, lung dryness cough, lung Yin deficiency and other symptoms, and can also be used to clear heat detoxification, diuretic detumescence and other symptoms. It can also be used to treat skin diseases and skin lesions, such as abrasions, burns, hypertrophic scars or eczema, as well as non-skin diseases, such as gastric ulcers and lesions of the gastric mucosa [2][3][4][5] . ...
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Centella asiatica, as a traditional medicinal herb, has a long history in traditional Chinese medicine. It contains various active ingredients such as flavonoids, triterpenoids, and polysaccharides, with pharmacological effects including antioxidant, anti-inflammatory, and immunomodulatory properties. Ultrasonic extraction technology, as a novel extraction method, can effectively extract active ingredients from Centella asiatica, thereby improving the quality and efficacy of the drug. Research has shown that ultrasonic extraction exhibits higher efficiency, shorter extraction time, and reduced solvent and energy consumption. By optimizing ultrasonic parameters and extraction processes, extraction efficiency can be improved, energy consumption reduced, providing scientific basis for further development and application of Centella asiatica.
... C. asitica healing small wounds, scratches, burns, hypertrophic wounds, and eczema [3,4], smoothing and improving skin condition [5]. C. asitica is also recommended for chronic venous insufficiency [6]; mental disability [7]; antinociceptive, antipyretic antibacterial, antiviral, anti-inflammatory [8]; and for improving cognition, relieving anxiety and anticancer agent [9]. ...
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Centella asiatica (L.) Urb. is a widely known medicinal plant for dermatological and non-dermatological diseases. The demand for C. asiatica extracts continues to increase but its availability is markedly depleted due to exploitation and limited cultivation. This study was conducted to evaluate the phosphate growth responses and variation of secondary metabolites production of C. asiatica cultivated at different phosphate application rates in acid soil in Indonesia. The soil pH used in this study was 2.76. Rates of phosphate application were 0 kg per plant as control plant, 20, 40, 60, 80 and 100 kg ha-1, respectively. Results showed that the plants applied with 40 kg ha-1 phosphate resulted in the highest number of leaves, petiole length, total leaf area, and number of tendrils and stolons which lead to the higher biomass. C. asiatica produced various types of secondary metabolites, i.e asiaticoside, madecassoside, asiatic acid, saponin, tannin, phenolic, flavonoid, triterpenoid, steroid, and glycoside. The production of secondary metabolites was optimized by the application of 20 kg ha-1 phosphate. It can be concluded that the application low dosage of phosphate can enhance the growth and secondary metabolites production of C. asiatica cultivated in acid soil. HIGHLIGHTS Gotu kola is well-known medicinal plant that has which has been used for generations and its benefits has been confrmed by the consumers Gotu kola can grow in both lowlands and highlands but the centellosides contents in gotu kola affected by the growing medium and phosphorus application The demand for simplicia is increasing, while the availability of gotu kola is limited in nature may cause gotu kola become rare and even endangered. Thus, it is necessary to cultivate gotu kola to maintain good quality and quantity The specific target to be achieved is the availability of gotu kola with optimal centelloside content GRAPHICAL ABSTRACT
... Centella asiatica has been commercialized as treatment for CVD (CENSIA, centella extract 30 mg, Dongkook Co., Republic of Korea) to improve the symptoms related to venous and lymphatic insufficiency (bluntness of lower extremities, pain, restless leg symptoms) (15). An interesting precaution for the use of CENSIA is the recommendation for short-term use. ...
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Chronic venous insufficiency (CVI) is a widespread condition affecting millions worldwide. Each year, approximately 150,000 new patients are diagnosed with CVI, and nearly $500 million is used in the care of these patients. Blood flow in the venous system has intact valves and muscle pumps to allow blood to flow back to the heart against gravity. The inadequacy of these systems leads to difficulties in blood circulation, resulting in blood reflux, blood pooling, and venous hypertension. The condition mentioned above can lead to the development of varicose veins, edema, discomfort, alterations in the skin, and potentially even the formation of ulcers. Conditions that induce CVI genetic predisposition, obesity (body mass index greater than 30), continuous standing/sitting work, age, pregnancy, gender, and lifestyle. Conventional venous insufficiency treatments include compression therapy, surgical interventions like vein stripping, and sclerotherapy. Venoactive drugs used in conservative treatment have the potential to enhance both varicose veins and symptoms associated with chronic venous disorders throughout all stages of venous insufficiency. In addition to synthetic drugs, naturally derived coumarins, flavonoids, rutin derivatives, pycnogenol, micronized purified flavonoid fraction, and saponosides are essential in the treatment. Medicinal plants and natural compounds are highly preferred for treating CVI and varicose veins due to their biological activities, such as anti-inflammatory, antioxidant, and vascular tone improvement. The present review provides a concise overview of the utilization of natural compounds and plant extracts in treating varicose veins, both in medical practice and traditional folk medicine.
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This chapter reviews the neuroimaging features of the potential effects of Centella asiatica use.Keywords Centella asiatica Subarachnoid hemorrhageIntracranial aneurysmReversible cerebral vasoconstriction syndromeLysergic acid
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Extracts of the leaves of gotu kola (Centella asiatica) and its most prominent constituent, asiaticoside, are undoubtedly beneficial in the treatment of skin injuries and diseases. The mechanism of action clearly involves stimulation of reticuloendothelial growth and inhibition of formation of collagen and acidic mucopolysaccharides, as well as a bacteriostatic effect. Good results have also been reported in the treatment of venous disease and hepatic fibrosis. The hydrophilic component of gotu kola leaf deserves closer evaluation of its potential for improving mental functioning, particularly in mentally deficient children, along with its CNS depressant activity. The Canadian regulatory status of C. asiatica extracts and asiaticoside as prescription drugs is insupportable, discouraging potentially beneficial treatments judged extremely safe by experimental data and the experience of human use.
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On the basis of a questionnaire investigation, a set of 319 patients with the manifestation of chronic venous disease was investigated for the occurrence of risk factors affecting the inception and development of lower limb venous system disease. The following risk factors appeared significantly more frequently in the set of patients: sex, occurrence of VV in the family (inherited disposition), overweight, pregnancy, all of them playing an important role in the development of chronic venous disease (CVD) in predisposed individuals.
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Centella asiatica, a medicinal herb widely distributed throughout the world is popular as a traditional medicine. In Ayurveda, it is used either alone or as an important ingredient of several formulations for the management of CNS, skin and gastrointestinal diseases. Several of its traditional uses have been scientifically validated and some of the active principles have also been reported. This review focuses on the details of its medicinal uses with emphasis on the pharmacological actions.
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Advanced chronic venous insufficiency (CVI) is an important health problem. In Hong Kong, with its predominantly Chinese population, most patients have primary CVI because deep vein thrombosis is less common. Nevertheless, 80% of the limbs with advanced CVI had reflux in both the superficial and deep vein systems. This showed that advanced CVI in this population is a multisystem pathological condition affecting both the superficial and deep vein systems. In the present study, it was hypothesized that the abnormal hydrostatic forces in the superficial and perforating vein systems are the significant pathologic forces leading to advanced CVI, although deep vein incompetence is common. This deep vein incompetence can be contributed to significantly by venous overload as a result of superficial reflux (reflux circuit of venous overload). This is well supported by the abolition of deep venous reflux as well as significant haemodynamic improvement as measured by air plethysmography after superficial vein surgery in limbs with mixed superficial and deep venous incompetence. Recently, subfascial endoscopic perforating vein surgery (SEPS) was introduced as a minimally invasive technique to interrupt incompetent calf perforators. Preliminary local experience showed that SEPS with concomitant superficial vein surgery was associated with a 97% ulcer healing at a mean follow up of 15 months. Significant haemodynamic improvement was also shown by air plethysmography. However, recurrent ulcers were noted in 15% of the limbs. Thus, SEPS with superficial vein surgery where appropriate can be the optimal operative treatment strategy for advanced CVI in the local population, although ulcer recurrence remains a concern.